The role of multimodality management in locally advanced non-small cell lung cancer (NSCLC) continues to evolve and is a subject of ongoing clinical research. Induction chemotherapy followed by surgical resection with or without thoracic radiotherapy has proved superior to surgical resection alone in patients with ipsilateral mediastinal (N2) disease. Whether surgery alone still plays a role in these patients is the subject of an ongoing intergroup study. As no definitive, optimal effective chemotherapy regimen currently exists for NSCLC, future studies will attempt to incorporate novel and active agents like the taxanes, irinotecan, vinorelbine, and gemcitabine into combined-modality therapy for locally advanced NSCLC. Thoracic radiation therapy by itself provides local control and effective palliation of tumor-related symptoms but has minimal impact on the survival of patients with locally advanced disease. Novel schemes such as hyperfractionated radiotherapy and continuous hyperfractionated accelerated radiotherapy are currently being investigated and appear promising but need to be tested in combination with chemotherapeutic agents. Randomized studies have demonstrated the benefit of concurrent or sequential chemoradiation in selected patients with a good performance status and minimal weight loss. The exact sequence of combined-modality therapy has yet to be determined. The combination of paclitaxel and platinum compounds has shown impressive activity in advanced NSCLC in both phase II and III randomized studies. We have incorporated weekly low-dose paclitaxel and carboplatin with concurrent thoracic radiation in treating patients with locally advanced, inoperable NSCLC, and long-term follow-up has shown remarkable survival rates. Confirmation of these phase II combined-modality studies is needed. Combination sequential chemotherapy followed by concurrent chemoradiation in patients with advanced NSCLC has the potential to improve overall survival by increasing both local and distant control.

Irradiation therapy for lung cancer is mostly restricted to conventional methods. To improve therapeutic ratio, we have combined a treatment planning and a gene therapy approach. Three-dimensional conformal radiotherapy is described as carried out by methods of gene therapy for radiation protection using the manganese-superoxide-dismutase transgene delivered by inhalation gene transfer. These methods may improve therapeutic outcomes in lung cancer.

Advances in cell and molecular biology have increased our understanding of the multiple events that lead to the development of lung cancer. The field cancerization theory suggests that multiple genetic abnormalities occur throughout the respiratory epithelium as a result of long-term carcinogen exposure. Because of this diffuse injury throughout the lung, systemic therapy that could halt or reverse the development of cancerous changes may be effective in preventing lung cancer. This article summarizes the chemoprevention agents that have been used in clinical trials to prevent lung cancer of the head and neck. Biomarkers that have been suggested as intermediate end points in evaluating the effectiveness of chemoprevention agents are also discussed.

Lung cancer, which is the leading cause of cancer mortality, remains a significant health-care problem among men and women in the United States, despite an overall 20-year decline in the incidence of cigarette smoking. Non-small cell lung cancer (NSCLC) comprises 75 to 80% of all lung cancer cases. The metastatic nature of this disease has been responsible for the poor survival statistics reported to date and emphasizes the need for effective systemic treatment. Prior to 1993, attempts to identify new chemotherapeutic agents and combinations with activity against NSCLC met with little success. Recently, however, several new compounds and classes of compounds have offered some hope for at least small improvements in response and survival while being relatively well tolerated in patients with this disease. This article presents current findings for some of these agents, including the taxanes paclitaxel and docetaxel, the topoisomerase inhibitors irinotecan and topotecan, and the novel pyrimidine analogue gemcitabine. In addition, the University of Southern California/Norris Cancer Center experience with the combination of carboplatin and paclitaxel is presented.

The Lung Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer was founded in 1981. During the past 15 years, the group has participated in the development of treatment of non-small cell lung cancer with chemotherapy. The group performed standard phase II studies of new drugs and phase III studies with new and active drugs. Furthermore, the group performed studies combining chemotherapy with treatment for localized disease.

The disappointing results obtained with currently available chemotherapy for lung cancer has led to the development of several new agents over the past 5 years. These include paclitaxel, docetaxel, vinorelbine, gemcitabine, and the camptothecins, irinotecan and topotecan. To date, phase I and II clinical trials with paclitaxel, docetaxel, gemcitabine, and combinations containing these drugs have been performed in patients with non-small cell lung cancer in Australia. These trials have produced overall response rates of 10 to 40%, which are similar to the rates obtained in other studies with these agents. In general, the agents have been well tolerated. However, these studies cannot be compared with previous studies employing conventional chemotherapeutic agents, primarily because the results of the former studies may have been skewed due to enrollment of younger, healthier patients and a variable proportion of patients with locally advanced rather than metastatic disease. Randomized controlled trials will be needed to determine whether use of these newer agents is associated with improvements in survival, palliation, and/or toxic reactions when compared with currently used regimens.

Non-small cell lung cancer (NSCLC) is refractory to systemic chemotherapy, compared with small cell lung cancer. Until recently, only five drugs--cisplatin, vindesine, mitomycin, ifosfamide, and vinblastine--could produce overall response rates of 15% against NSCLC. However, recent efforts have contributed to the development of new drugs with activity against NSCLC, including irinotecan hydrochloride (CPT-11), paclitaxel, docetaxel, vinorelbine, and gemcitabine. Combination chemotherapy against NSCLC using these agents has demonstrated high response rates. In Japan, various combination chemotherapy and combined-modality regimens employing CPT-11 have been evaluated for their efficacy. Randomized controlled trials to establish new state-of-the-art treatments for NSCLC are ongoing.

Eastern Cooperative Oncology Group (ECOG) investigators have tested a variety of single-agent and combination regimens in patients with non-small cell lung cancer (NSCLC) during the last 2 decades. The following observations have been made. (1) The mitomycin/vinblastine/cisplatin regimen produced a trend for higher response rates in two studies and a significantly higher response rate in a third study. Survival, however, tended to be shorter in patients receiving this regimen. (2) Carboplatin produced a 9% overall response rate and a median survival of 31.7 weeks, which was slightly but significantly longer than the median survivals obtained with three combination chemotherapy regimens. (3) Paclitaxel produced an overall response rate of 21% and a 1-year survival rate of 40% in previously untreated NSCLC patients. This observation led to a phase III trial in which paclitaxel (135 mg/m2 and 250 mg/m2) was combined with cisplatin and compared with etoposide/cisplatin. Response rates for each of the paclitaxel/cisplatin regimens (26% for 135 mg/m2 paclitaxel and 31% for 250 mg/m2) were significantly higher than the response rate for etoposide/cisplatin (12%), but response between the two paclitaxel/cisplatin arms was not significantly different. At this point, there is a trend toward longer survival in each of the paclitaxel/cisplatin arms, but the final survival analyses have not been completed. In the next phase III trial, ECOG will evaluate paclitaxel (135 mg/m2) plus cisplatin in comparison to three other regimens--docetaxel/cisplatin, gemcitabine/cisplatin, and carboplatin/paclitaxel.

Video-assisted thoracic surgery (VATS) has enabled more complex procedures previously requiring thoracotomy to be accomplished in lung cancer management. VATS today can be employed in the evaluation of idiopathic (and known) malignant pleural effusions, mediastinal adenopathy, indeterminate pulmonary nodules, and compromise resection and lobectomy of peripheral stage I non-small cell lung cancer. Thus, VATS is becoming an accepted approach to a variety of intrathoracic problems, although its absolute indications for patients with lung cancer have yet to be firmly defined. This article reviews the authors' current experience with VATS procedures in the treatment of patients with lung cancer.

Resection of indeterminate pulmonary lesions in patients with a history of malignancy is indicated, as the presence of metastases will provide prognostic information and often dictate further therapy. Pulmonary metastasectomy also improves survival in select patients with favorable tumor histologies. We reported the results of video-assisted thoracoscopic surgery (VATS) resection of indeterminate lung nodules in 72 patients with a history of malignancy. All lesions identified on preoperative high-resolution CT scan were found at surgery with visual inspection, digital palpation, or (in 13 cases) CT-guided needle localization. All lesions were resected nonanatomically with a rim of normal parenchyma, as is done with open techniques; 63 patients were found to have metastases and 9 patients had benign disease. There was no mortality, minimal morbidity, and decreased hospital stays in patients undergoing VATS resection compared with historical control subjects. These data and other reports have led to the widespread use of VATS for patients undergoing resection to establish a diagnosis. The role of VATS in patients with favorable tumor histology and limited tumor burden for whom metastasectomy may result in a survival advantage remains controversial. Improved image resolution with spiral CT scans and digital palpation, combined with intraoperative ultrasound examination of the lung, may decrease or eliminate the number of lesions missed with a VATS approach. The role of therapeutic VATS metastasectomy remains to be defined. Thus, this procedure currently should be used only in clinical trials.

The clinical manifestations of antiphospholipid antibody syndrome (APLAS) are protean. Pulmonary manifestations are often thromboembolic in origin; ARDS and pulmonary hypertension have been reported as features of a widespread vasculopathy associated with systemic lupus or Sjögren's syndrome. This is the report of a woman with primary APLAS who died of a noninflammatory pulmonary vasculopathy. The case is unusual in its pulmonary manifestations, its initial response to corticosteroids and antithrombotic medications, its failure to stabilize with high-intensity warfarin sodium and aspirin treatment, and finally its fulminant progression despite multiple interventions.

Paraneoplastic pemphigus (PNP) is an autoimmune disease associated with leukemia and non-Hodgkin's lymphoma. A patient with stage IVB poorly differentiated lymphocytic lymphoma developed characteristic upper and lower airway involvement with profound mucocutaneous erosion and tracheobronchial epithelial desquamation. Immunofluorescence testing confirmed autoantibody deposition along the basement membrane of bronchial epithelium. Disruption of the cellular adhesion mechanisms, including desmosomes, hemidesmosomes, and possibly the integrin subunits, is presumed to have led to disruption and desquamation of the tracheobronchial epithelial barrier, severe obstruction of the airways and hypoxia, and possibly bacterial superinfection. As far as can be determined, the feature of airflow obstruction occurring in association with PNP has not been described. Physicians should be aware that these complications of PNP may rapidly lead to hypoxic respiratory failure and death.

Relapsing polychondritis (RP) is a rare disease characterized by recurrent inflammation and destruction of the cartilaginous structures. Tracheobronchial chondritis is a dreaded complication of RP. We wish to report a case of RP of the trachea and bronchi which was treated with nasal continuous positive airway pressure.

A patient with alpha1-antitrypsin deficiency is reported herein; this subject developed aggressive bronchial disease and recurrent cutaneous vasculitis after pulmonary infection with Pseudomonas aeruginosa. Autoantibodies to neutrophil cytoplasmic antigens were detected, which produced granular cytoplasmic staining by indirect immunofluorescence with specificity for a newly characterized antigen: bactericidal/permeability-increasing protein (BPI). The bronchial disease and vasculitis improved, and the IgA anti-BPI titer fell after antipseudomonal treatment. This raises the possibility that anti-BPI antibodies contributed to both the bronchial disease and vasculitis.

Phenytoin hypersensitivity syndrome (PHS) is a rare delayed hypersensitivity reaction which occurs following exposure to phenytoin sodium. Pulmonary involvement is uncommonly described. Herein is reported the first case of histopathologic bronchiolitis obliterans organizing pneumonia (BOOP) found on open-lung biopsy in a patient with severe PHS. New onset, clinically significant, cold agglutinin disease was also documented. Hemodynamic parameters mimicking sepsis were present in the absence of significant clinical infection. Rapid, dramatic improvement followed high-dose steroid therapy.

Aberrant origin of the right subclavian artery occurs in up to 1% of the population and can result in a wide range of symptoms. In this report, two cases of this anomaly are presented. In the first case, a patient developed fatal group A streptococcal aortitis. In the second case, the patient complained of chronic cough and intermittent dyspnea. The embryologic genesis of this abnormality is discussed and the current literature is summarized. Although relatively uncommon, it is important to consider this vascular anomaly in the differential diagnosis of patients with dysphagia, dyspnea, chest pain, fever, or mediastinal widening evidenced on chest roentgenography.

An unusual case of life-threatening visceral larva migrans (toxocariasis) is reported herein. The patient was admitted with acute dyspnea and bilateral pleural effusion; rapidly pericardial tamponade developed. Blood and body fluid eosinophilia were elevated. Extensive investigations revealed no malignant process or vasculitis, but Toxocara infection was confirmed by rising specific antibody titers. The high seroprevalence of Toxocara antibodies, particularly in children, suggests that a diagnosis of visceral larva migrans should be considered before a diagnosis of systemic hypereosinophilic syndrome even when clinical presentation is unusual. Prophylaxis against this widespread polymorphic zoonotic infection is desirable in view of the potentially dramatic consequences of infestation.

Cholesterol crystal embolization (CCE) has been documented to affect nearly every organ system. However, CCE involving the lung is distinctly uncommon and has been documented only in the setting of an aortocaval fistula.

Over a period of years, insulin-dependent diabetes and respiratory insufficiency developed in a 35-year-old patient with end-stage cystic fibrosis. After waiting more than 4 years while receiving maintenance treatment with continuous liquid O2 and nasal ventilation, the patient underwent double-lung and pancreatic islet cell transplantation. Subsequently, the patient has enjoyed a normal life with full employment and much better control of his diabetes. Pancreatic islet cell transplantation is a simple and innocuous technique easily added to the end of lung transplantation. These new pancreatic cells, although locally injected, are still secreting more than 2 years later as assessed by repeated C-peptide measurements.

A diagnosis of severe stridor due to a subglottic tracheal mass was made in a 62-year-old woman. The tumor was removed by external transtracheal surgery, and the pathologic study disclosed that it was intratracheal ectopic thyroid tissue. In this particular case, 10 years prior to the onset of the stridor, normal thyroid tissue was seen in biopsy specimens of the same subglottic localization. Although the pathogenesis of a mass composed of intratracheal thyroid tissue is not known, this case shows that it can be a slowly progressive tumor that is asymptomatic for several years.